Encorafenib (2) – Braftovi®

• Clinical trials
  • The BEACON CRC trial is a 3-arm, open-label, international, randomised trial comparing encorafenib + cetuximab and encorafenib + binimetinib + cetuximab in the intervention arms with cetuximab + irinotecan or cetuximab + FOLFIRI in the control arm.

Adult patients with metastatic colorectal cancer harbouring a BRAF V600E mutation who have received at least one prior systemic therapy

• For adult patients with metastatic colorectal cancer harbouring a BRAF V600E mutation who have received at least one prior systemic therapy, there is a hint of considerable additional benefit.
• Overall, based on the available results from the BEACON CRC trial, there is a hint of considerable additional benefit for encorafenib + cetuximab compared with irinotecan + cetuximab or FOLFIRI + cetuximab.
• Consequently, the overall certainty of the evidence regarding additional benefit (probability of additional benefit) is classified as a hint.
• mortality
  • overall survival
  • The BEACON CRC study demonstrates a statistically significant prolongation of overall survival with treatment using encorafenib + cetuximab compared with irinotecan + cetuximab or FOLFIRI + cetuximab.
  • Taking into account the poor survival prognosis for patients with BRAF-mutated tumours, as well as the advanced stage of the disease and treatment, the extent of the prolongation achieved in overall survival is assessed as a significant improvement in therapeutic benefit.
• Morbidity – Progression-free survival (PFS)
  • PFS was assessed as a secondary endpoint in the BEACON CRC trial and is defined as the time from randomisation to the date of disease progression or death from any cause, whichever occurs first.
  • The results show a statistically significant prolongation of PFS with treatment using encorafenib + cetuximab compared with irinotecan + cetuximab or FOLFIRI + cetuximab.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms
  • Patients’ symptoms were assessed in the BEACON CRC trial using the symptom scales of the EORTC QLQ-C30 questionnaire and the PGIC (Patient Global Impression of Change) questionnaire.
  • The MMRM analyses of symptoms show that patients treated with encorafenib + cetuximab experienced a significantly minor burden from the symptom ‘diarrhoea’.
  • Statistically significant differences in the mean change were observed for the symptoms of nausea and vomiting, loss of appetite and constipation. However, the 95% confidence intervals for the standardised mean difference (Hedges’ g) do not lie entirely outside the non-significant range of -0.2 to 0.2. Consequently, it cannot be concluded with sufficient certainty that the effects in each case are clinically relevant.
• Health-related quality of life
  • Health-related quality of life was assessed in the BEACON CRC study using the functional scales of the EORTC QLQ-C30 questionnaire and the FACT-C questionnaire.
  • A statistically significant advantage for the intervention arm is evident in the mean change in the overall score of the tumour-generic FACT-G questionnaire and, in particular, in the physical well-being endpoint. However, the 95% confidence interval for the standardised mean difference (Hedges’ g) does not lie entirely outside the irrelevance range of -0.2 to 0.2. Consequently, it cannot be concluded with sufficient certainty that the effects are clinically relevant in each case.
  • In the functional scales of the EORTC QLQ-C30 questionnaire, a statistically significant difference was observed in the mean change for the ‘global health status’ endpoint. However, the 95% confidence intervals for the standardised mean difference (Hedges’ g) do not lie entirely outside the irrelevance range of -0.2 to 0.2. Consequently, it cannot be concluded with sufficient certainty that the effects are clinically relevant in each case.
  • Overall, therefore, neither an advantage nor a disadvantage to health-related quality of life can be inferred for encorafenib + cetuximab.
• Side effects – serious adverse events
  • With regard to patients affected by serious AEs, the time-to-event analysis shows a statistically significant difference in favour of encorafenib + cetuximab.
• Overall assessment / Conclusion
  • Treatment with encorafenib plus cetuximab was associated with a statistically significant prolongation of overall survival, the extent of which, given the poor survival prognosis for patients with BRAF-mutated tumours as well as the advanced stage of disease and treatment, is assessed as a significant improvement in therapeutic benefit.
  • In the morbidity endpoint category, an advantage for encorafenib + cetuximab is evident, based on a significantly minor burden caused by the symptom ‘diarrhoea’.
  • In the health-related quality of life endpoint category, neither an advantage nor a disadvantage in health-related quality of life can be inferred for encorafenib plus cetuximab.
  • The results regarding side effects show exclusively positive effects for encorafenib + cetuximab. Consequently, a significant improvement in side effects is observed with treatment using encorafenib + cetuximab compared with irinotecan + cetuximab or FOLFIRI + cetuximab.
• Overall assessment / Conclusion
  • Treatment with encorafenib plus cetuximab is associated with a statistically significant prolongation of patients’ overall survival; the extent of which, given the poor survival prognosis for patients with BRAF-mutated tumours and the advanced stage of the disease and treatment, is assessed as a significant improvement in therapeutic benefit.
  • In the morbidity endpoint category, an advantage for encorafenib + cetuximab is evident based on a significantly minor burden associated with the symptom ‘diarrhoea’.
  • In the health-related quality of life endpoint category, neither an advantage nor a disadvantage in health-related quality of life can be inferred for encorafenib plus cetuximab.
  • The results regarding side effects show exclusively positive effects for encorafenib + cetuximab. Consequently, a significant improvement in side effects is observed with treatment using encorafenib + cetuximab compared with irinotecan + cetuximab or FOLFIRI + cetuximab.

Courtesy translation only, please refer to the German original.